US7998978B2 - Substituted 2-amino-fused heterocyclic compounds - Google Patents

Substituted 2-amino-fused heterocyclic compounds Download PDF

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US7998978B2
US7998978B2 US12/299,381 US29938107A US7998978B2 US 7998978 B2 US7998978 B2 US 7998978B2 US 29938107 A US29938107 A US 29938107A US 7998978 B2 US7998978 B2 US 7998978B2
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Liming Huang
Song Liu
Elizabeth A. Lunney
Simon P. Planken
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Pfizer Corp SRL
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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Definitions

  • the present invention relates to novel substituted 2-amino-fused heterocyclic compounds, such as 2-amino-quinolines, 2-amino-isoquinolines, and 2-amino-quinazolines, compounds of formula (I), to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in the preparation of a medicament for use in the treatment or prevention of a disease or medical condition mediated through c-Jun N-terminal kinases (JNKs), leading to a decreased glucose threshold for insulin secretion.
  • JNKs c-Jun N-terminal kinases
  • the compounds are predicted to lower blood glucose by increasing hepatic glucose uptake. Such compounds may have utility in the treatment of Type 2 diabetes and obesity.
  • JNKs c-Jun N-terminal kinases
  • SAPK stress activated protein kinase
  • the JNK signal transduction system of stress response MAP kinase family system is activated by changes in osmotic pressure, DNA damage, anisomycine, heat shock, ultraviolet radiation, ischemia, inflammatory cytokines and the like and various stress stimulations relating to apoptosis induction, it is considered to constitute a major intracellular information transduction path responsible for stress response (Biochemica et Biophysica Acta, vol. 1333, pp. F85-F104 (1997)). From an experiment using a JNK1 deletion mouse, JNK is reported to be an important mediator involved in obesity and insulin resistance (Nature, vol. 420, pp. 333-336 (2002)).
  • the present invention relates to a compound of formula (I):
  • Z 1 is CH or N
  • Ring A is a 5- or 6-membered ring which may optionally contain at least one heteroatom
  • R 1 is hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —(C ⁇ O)—R 3 , —(C ⁇ O)—(CR 3 R 4 ) q —O—(CR 3 R 4 ) p —R 3 , —(C ⁇ O)—(CR 3 R 4 ) q —O—(CR 3 R 4 ) p —(C ⁇ O)—R 3 , —(C ⁇ O)—NR 3 R 4 , —(CR 3 R 4 ) q —NR 3 —(C ⁇ O)R 4 , —(C ⁇ O)—(CR 3 R 4 ) q —NR 3 —(C ⁇ O)—R 4 , —(C ⁇ O)—(CR 3 R 4 ) q —NR 3 —(C ⁇ O)—R 4 , —(C ⁇ O)—(CR 3 R 4 ) q —NR 3 —(C ⁇
  • R 2 is H, halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C ⁇ O)—R 5 , —(C ⁇ O)—O—R 5 , —O—(C ⁇ O)—R 5 , —NR 5 (C ⁇ O)—R 7 —(C ⁇ O)—NR 5 R 6 , —NR 5 R 6 , —NR 5 OR 6 , —S(O) k NR 5 R 6 , —S(O) j (C 1 -C 6 )alkyl, —O—SO 2 —R 5 , —NR 5 —S(O) k —R 6 —(CR
  • each of R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from H, (C 1 -C 6 )alkyl, —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 6 -C 10 )aryl, and —(CR 8 R 9 ) p (4-10)-membered heterocyclyl;
  • any carbon atoms of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl moieties of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are optionally substituted with 1 to 3 R 11 substituents each independently selected from oxo, halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C ⁇ O)—R 8 , —(C ⁇ O)—O—R 8 , —O—(C ⁇ O)—R 8
  • any carbon atoms of each of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl moieties of the foregoing R 11 are optionally substituted with 1 to 3 R 12 substituents each independently selected from halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C ⁇ O)—R 8 , —(C ⁇ O)—O—R 8 , —O—(C ⁇ O)—R 8 , —NR 8 (C ⁇ O)—R 10 , —(C ⁇ O)—NR 8
  • any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , and R 12 are optionally substituted with 1 to 3 R 13 substituents each independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C ⁇ O)—R 8 , —(C ⁇ O)—R 9a , —(C ⁇ O)—O—R 8 , —(C ⁇ O)—NR 8 R 9 , —(CR 8 R 9 ) q —NR 8 R 9 , —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 6 -C 10 aryl), —(CR 8 R 9 ) p (4-10)-membere
  • each R 8 , R 9 , and R 10 are independently H or (C 1 -C 6 )alkyl
  • each R 9a is independently —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 6 -C 10 aryl), or —(CR 8 R 9 ) p (4-10)-membered heterocyclyl;
  • p, q, and v are each independently 0, 1, 2, 3, 4, or 5;
  • n and j are each independently 0, 1, or 2;
  • t is 1, 2, 3, or 4;
  • w 1, 2, or 3
  • k 1 or 2.
  • the invention relates to compounds of the formula (I) selected from the group consisting of:
  • Z 1 is CH or N
  • Z 2 , Z 3 , Z 4 , and Z 5 are each independently C or N;
  • Z 6 , Z 7 , and Z 8 are each independently C, S, O, or N;
  • R 2 attached to any of Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , and Z 8 is independently selected from the group consisting of H, halo, cyano, nitro, —CF 3 , —CHF 2 , —CH 2 F, trifluoromethoxy, azido, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C ⁇ O)—R 14 , —(C ⁇ O)—O—R 14 , —O—(C ⁇ O)—R 14 , —NR 14 (C ⁇ O)—R 15 , —(C ⁇ O)—NR 14 R 15 , —NR 14 R 15 , —NR 14 OR 15 , —S(O) k NR 14 R 15 , —S(O) j R 14 ,
  • each of R 14 and R 15 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 6 -C 10 )aryl, and —(CR 8 R 9 ) p (4-10)-membered heterocyclyl.
  • the invention relates to compounds of the formula (Ia) selected from the group consisting of:
  • the invention relates to compounds of the formula (Ib) selected from the group consisting of:
  • the invention relates to compounds of the formula (Ia), specifically compound of formula (Ia1):
  • the invention relates to compounds of the formula (II):
  • ring B is selected from —(CR 3 R 4 ) v (3-10)-membered cycloalkyl, —(CR 3 R 4 ) v (C 6 -C 10 )aryl, —(CR 3 R 4 ) v (4-10)-membered heterocyclyl, —(CR 3 R 4 ) q (C ⁇ O)(CR 3 R 4 ) v (3-10)-membered cycloalkyl, —(CR 3 R 4 ) q (C ⁇ O)(CR 3 R 4 ) v (C 6 -C 10 )aryl, and —(CR 3 R 4 ) q (C ⁇ O)(CR 3 R 4 ) v (4-10)-membered heterocyclyl.
  • the invention relates to compounds of the formula (I), wherein R 2 is H, halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —(C ⁇ O)—R 5 , —(C ⁇ O)—NR 5 R 6 , —(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) v (C 6 -C 10 aryl), —(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q O(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) q O(CR 5 R 6 ) v (C 6 -C 10 )aryl, or —(CR 5 R 6 ) q O(CR 5 R 6 ) v (4-10)-membered heterocyclyl.
  • the invention relates to compounds of the formula (I), wherein R 2 is —(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) v (C 6 -C 10 aryl), —(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q (C ⁇ O)(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) q (C ⁇ O)(CR 5 R 6 ) v (C 6 -C 10 )aryl, —(CR 5 R 6 ) q (C ⁇ O)(CR 5 R 6 ) v (4-10)-membered heterocyclyl, —(CR 5 R 6 ) q O(CR 5 R 6 ) v (3-10)-membered cycloalkyl, —(CR 5 R 6 ) q O(CR 5 R 6 )
  • the invention relates to compounds of the formula (I), wherein R 2 is pyrazolyl wherein any nitrogen atoms of the pyrazolyl are optionally substituted with (C 1 -C 6 )alkyl, —(CR 8 R 9 ) p (C 6 -C 10 aryl), —(CR 8 R 9 ) p (4-10)-membered heterocyclyl, —(CR 8 R 9 ) q (C ⁇ O)(CR 8 R 9 ) p (C 6 -C 10 )aryl, or —(CR 8 R 9 ) q (C ⁇ O)(CR 8 R 9 ) p (4-10)-membered heterocyclyl.
  • the invention relates to compounds of the formula (I), wherein R 2 is —(C ⁇ O)—NR 5 R 6 , wherein each of R 5 and R 6 are independently selected from H, (C 1 -C 6 )alkyl, —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, —(CR 8 R 9 ) p (C 6 -C 10 )aryl, and —(CR 8 R 9 ) p (4-10)-membered heterocyclyl.
  • the invention relates to compounds of the formula (I), wherein R 1 is (C 1 -C 6 )alkyl, —(CR 3 R 4 ) v (3-10)-membered cycloalkyl, —(CR 3 R 4 ) v (C 6 -C 10 aryl), or —(CR 3 R 4 ) v (4-10)-membered heterocyclyl.
  • the invention relates to compounds of the formula (I), wherein R 1 is —(CR 3 R 4 ) v (3-10)-membered cycloalkyl, —(CR 3 R 4 ) v (C 6 -C 10 aryl), —(CR 3 R 4 ) v (4-10)-membered heterocyclyl, —(CR 3 R 4 ) q (C ⁇ O)(CR 3 R 4 ) v (3-10)-membered cycloalkyl, —(CR 3 R 4 ) q (C ⁇ O)(CR 3 R 4 ) v (C 6 -C 10 )aryl, —(CR 3 R 4 ) q (C ⁇ O)(CR 3 R 4 ) v (4-10)-membered heterocyclyl, —(CR 3 R 4 ) q S(O) j (CR 3 R 4 ) v (C 6 -C 10 )aryl, or —(CR 3 R 4 ) q S(O)
  • the invention relates to compounds of the formula (I), wherein any carbon atoms of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl moieties of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are optionally substituted with 1 to 3 R 11 substituents each independently selected from halo, cyano, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —(C ⁇ O)—R 8 , —NR 8 (C ⁇ O)—R 10 , —(C ⁇ O)—NR 8 R 9 , —(C ⁇ O)—NR 8 R 9a , —NR 8 R 9 , —S(O) j R 8 , —NR 8 —S(O) k —
  • the invention relates to compounds of the formula (I), wherein any carbon atoms of the (C 1 -C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -C 10 )aryl and the (4-10)-membered heterocyclyl moieties of the foregoing R 11 are optionally substituted with 1 to 3 R 12 substituents each independently selected from halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, and —NR 8 R 9 .
  • the invention relates to compounds of the formula (I), wherein any nitrogen atoms of the (4-10)-membered heterocyclyl of the foregoing R 1 , R 2 , and R 11 are optionally substituted with 1 to 3 R 13 substituents each independently selected from (C 1 -C 6 )alkyl, —(C ⁇ O)—R 8 , —(C ⁇ O)—R 9a , —(C ⁇ O)—O—R 8 , —(C ⁇ O)—NR 8 R 9 , —(CR 8 R 9 ) q —NR 8 R 9 , —(CR 8 R 9 ) p (3-10)-membered cycloalkyl, and —(CR 8 R 9 ) p (C 6 -C 10 aryl), —(CR 8 R 9 ) p (4-10)-membered heterocyclyl.
  • the invention relates to compounds of the formula (I), wherein R 1 is optionally substituted —(CR 3 R 4 ) q (C ⁇ O)(CR 3 R 4 ) v (4-10)-membered heterocyclyl selected from the group consisting of:
  • the invention relates to compounds of the formula (I), wherein R 1 is optionally substituted —(CR 3 R 4 ) q (C ⁇ O)(CR 3 R 4 ) v (C 6 -C 10 )aryl selected from the group consisting of:
  • the invention relates to compounds of the formula (I), wherein R 1 is optionally substituted —(C ⁇ O)—R 3 , —(C ⁇ O)—(CR 3 R 4 ) q —O—(CR 3 R 4 ) p —R 3 , —(C ⁇ O)—(CR 3 R 4 ) q —O—(CR 3 R 4 ) p (C ⁇ O)—R 3 , —(C ⁇ O)—NR 3 R 4 , (C ⁇ O)—(CR 3 R 4 ) q —NR 3 —(C ⁇ O)—R 4 , or —(C ⁇ O)—(CR 3 R 4 ) q —(C ⁇ O)—NR 3 R 4 .
  • the invention relates to compounds of the formula (I), wherein R 1 is selected from the group consisting of:
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of compounds of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method of treating a condition that is mediated by the modulation of JNK, the method comprising administering to a mammal an effective amount of compounds of the formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also relates to a method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of compounds of the formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also relates to a method of treating chronic or acute cardiac failure, cardiac hypertrophy, dilated, hypertrophic or restrictive cardiomyopathy, acute myocardial infarction, post-myocardial infarction, acute or chronic myocarditis, diastolic dysfunction of the left ventricle, systolic dysfunction of the left ventricle, hypertension and nephropathy and nephritis as complications thereof, endothelial dysfunction, arteriosclerosis or post-angioplasty restenosis, which comprises administering an effective amount of compounds of the formula (I) to a mammal in need thereof.
  • the present invention also relates to a method of treating chronic rheumatoid arthritis, osteoarthritis, gout, chronic obstructive pulmonary disease, asthma, bronchitis, cystic fibrosis, inflammatory bowel disease, irritable colon syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, multiple sclerosis, eczema, dermatitis, hepatitis, glomerulonephritis, diabetes, ophthalmic diseases, diabetic retinopathy, diabetic macular edema, diabetic nephropathy, diabetic neuropathy, obesity, psoriasis or cancer, which comprises administering an effective amount of compounds of the formula (I) to a mammal in need thereof.
  • the present invention also relates to a method of treating Alzheimer's disease, Huntington's chorea, Parkinson's syndrome, epilepsy, amyotrophic lateral sclerosis, peripheral neuropathy, neurodegenerative disease or spinal injury, which comprises administering an effective amount of compounds of the formula (I) to a mammal in need thereof.
  • the present invention also relates to a method of treating cerebral apoplexy, cerebrovascular disorder, an ischemic disorder of an organ selected from the heart, kidney, liver and brain, ischemia-reperfusion injury, organ failure, endotoxin shock or rejection in transplantation, which comprises administering an effective amount of compounds of the formula (I) to a mammal in need thereof.
  • halo as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
  • alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety.
  • alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
  • alkoxy as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above.
  • Me means methyl
  • Et means ethyl
  • Ac means acetyl
  • cycloalkyl refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, preferably 5-8 ring carbon atoms.
  • exemplary cycloalkyls include monocyclic rings having from 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
  • Illustrative examples of cycloalkyl are derived from, but not limited to, the following:
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
  • (4-12)-membered heterocyclyl” or “(4-10)-membered heterocyclyl”, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 3-7, 6-10, or 4-10 atoms, respectively, in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is quinolinyl.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithio
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • the 4-7 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring.
  • heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl.
  • 4-7 membered heterocyclic are derived from, but not limited to, the following:
  • oxo refers to ⁇ O.
  • solvate is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine.
  • phrases “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula (I).
  • the compounds of formula (I) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula (I) are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyls
  • liver is a target organ
  • diabetes hepatitis, liver cancer, liver fibrosis, and malaria.
  • Methodabolic syndrome means psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.
  • R 5 , R 6 , R 8 and R 9 may vary with each iteration of v or p.
  • v or p is 2
  • the terms (CR 5 R 6 ) v or (CR 8 R 9 ) p may equal —CH 2 CH 2 —, or —CH(CH 3 )C(CH 2 CH 3 )(CH 2 CH 2 CH 3 )—, or any number of similar moieties falling within the scope of the definitions of R 5 , R 6 , R 8 and R 9 .
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • modulate refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
  • “obese” is defined, for males, as individuals whose body mass index is greater than 27.8 kg/m 2 , and for females, as individuals whose body mass index is greater than 27.3 kg/m 2 .
  • the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity.
  • inflammatory disorders refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.
  • terapéuticaally effective amount refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
  • amount . . . effective to lower blood glucose levels refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a concentration typically falls in the range of about 10 nM up to 2 ⁇ M; with concentrations in the range of about 100 nM up to 500 nM being preferred.
  • concentrations typically falls in the range of about 10 nM up to 2 ⁇ M; with concentrations in the range of about 100 nM up to 500 nM being preferred.
  • the activity of different compounds which fall within the definition of Formula (I) as set forth above may vary considerably, and since individual subjects may present a wide variation in severity of symptoms, it is up to the practitioner to determine a subject's response to treatment and vary the dosages accordingly.
  • insulin resistance refers to the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus.
  • insulin resistance syndrome refers to the cluster of manifestations that include insulin resistance, hyperinsulinemia, non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, and dyslipidemia.
  • NIDDM non insulin dependent diabetes mellitus
  • Certain compounds of formula (I) may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula (I), and mixtures thereof, are considered to be within the scope of the invention.
  • the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof.
  • the compounds of formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
  • Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds of the present invention and pharmaceutically acceptable salts or solvates of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • Isotopically labeled compounds of formula (I) of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compound of formula (I) may be prepared by reacting compounds (A-1) with a suitable —R 1 delivering agents (e.g. phenylacetyl carboxylic acid) in a suitable solvent (e.g. N,N-dimethylformamide) at a temperature between ⁇ 20 and 200 degrees Celcius.
  • a suitable —R 1 delivering agents e.g. phenylacetyl carboxylic acid
  • a suitable solvent e.g. N,N-dimethylformamide
  • Compound (A-2) may be obtained by reacting compound (A-3) with a suitable deprotecting agent (e.g. sulfonic acid) in a suitable solvent (e.g. water) at a temperature between ⁇ 78 and 100 degrees Celcius.
  • a suitable solvent e.g. water
  • Compound (A-3) may be obtained by reacting compound (A-4) with a compound of formula (A-5) in a suitable solvent (e.g. methanol) at a temperature between 0 and 200 degrees Celcius.
  • Compound (A-4) may be obtained by reacting compound (A-6) with an ether salt (e.g.
  • the compound of formula (I) may also be prepared by reacting compounds (B-2) with a compound of formula (B-1) (e.g. 6-(1H-pyrazol-4-yl)-isoquinolin-3-ylamine) in a suitable solvent (e.g. N,N-dimethylacetamide) at a temperature between 0 and 200 degrees Celcius.
  • a suitable solvent e.g. N,N-dimethylacetamide
  • Compounds of formula (B-2) may be prepared by reacting compound (B-3) under a suitable hydrolysis condition (e.g. HCl/H 2 O/SnCl 2 ) in a suitable solvent (e.g. acetic acid) at a temperature between 0 and 150 degrees Celcius.
  • Compound (B-3) may be obtained by reacting compound (B-4) with a suitable agent (e.g. Me 3 SiCN/ZnI) in a suitable solvent (e.g. toluenene and acetonitrile) at a temperature between 0 and 100 degrees Celcius.
  • a suitable agent e.g. Me 3 SiCN/ZnI
  • a suitable solvent e.g. toluenene and acetonitrile
  • Compound (B-4) may be obtained by reacting compound (B-5) with an oxidizing agent (e.g. CrO 3 /Pyridine) in a suitable solvent (e.g. water) at a temperature between ⁇ 20 and 50 degrees Celcius, followed by treatment of a acid (e.g. H 2 SO4) in a suitable solvent (e.g. pentane) at a temperature between 0 to 150 degree Celcius.
  • an oxidizing agent e.g. CrO 3 /Pyridine
  • Compound (B-5) may be obtained by reacting compound (B-6) with an organometallic reagent (e.g. CH 2 ⁇ CHMgBr) in a suitable solvent (e.g. tetrhydrofuran) at a temperature between ⁇ 20 and 100 degrees Celcius.
  • organometallic reagent e.g. CH 2 ⁇ CHMgBr
  • suitable solvent e.g. tetrhydrofuran
  • the compound of formula (I) may be prepared by reacting compounds (C-1) with a reagent such as HCl in a suitable solvent mixture (e.g. aqueous tetrahydrofuran) at a temperature between 0 and 150 degrees Celcius.
  • a suitable solvent mixture e.g. aqueous tetrahydrofuran
  • Compounds of formula (C-1) may be prepared by reacting compound (C-2) with a suitable —R 1 delivering agent (e.g. cyclohexyl bromide) and a bass such as sodium hydride in a suitable solvent (e.g. N,N-dimethylformamide) at a temperature between 0 and 200 degrees Celcius.
  • the compound of formula (I) may be prepared by reacting compounds (D-1) with a R 2 delivering agent (e.g., ethylamine) in a suitable solvent (e.g. isopropanol) at a temperature between 0 and 150 degrees Celcius. Under some cases, a condition of microwave heating is needed at a temperature between 50 to 200 degree Celcius.
  • Compounds of formula (D-1) may be prepared by reacting compound (D-2) with a R 1 delivering agent (e.g. methyl iodide) and a bass such as Cs 2 CO 3 in a suitable solvent (e.g. acetonitrile) at a temperature between 0 and 100 degrees Celcius.
  • Compounds of formula (D-2) may be prepared by reacting compound (D-3) with hydrazine in a suitable solvent mixture (e.g. water and tetrahydrofuran) at a temperature between 0 and 150 degrees Celcius.
  • a suitable solvent mixture e.g. water and tetrahydrofuran
  • Compounds of formula (D-3) may be prepared by reacting compound (D-4) with POCl 3 in a suitable solvent (e.g. toluene) at a temperature between 0 and 150 degrees Celcius.
  • Compounds of formula (D-4) is commercially available.
  • the compound of formula (I) may be prepared by reacting compounds (E-1) under a standard amide coupling conditions and/or methods known in the art (such as 1-(3-(dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (EDCl), butyl alcohol, with a suitable base such as N-methylmorpholine (NMM) to afford the compound of formula (I).
  • a suitable base such as N-methylmorpholine (NMM)
  • Compounds of formula (E-1) may be prepared by reacting the 2-amino quinazolines compound (E-2) under hydrolysis conditions known in the art (such as aqueous sodium hydroxide in methanol).
  • Compounds of formula (E-2) may be prepared by reacting compounds of type (E-3) with various amines in a suitable solvent (such as acetonitrile) with a suitable base (such as 1,8-diaza-bicyclo-[5.4.0]-undec-7-ene (DBU)).
  • a suitable solvent such as acetonitrile
  • a suitable base such as 1,8-diaza-bicyclo-[5.4.0]-undec-7-ene (DBU)
  • Compounds of formula (E-3) may be prepared via selective dehalogenation of compounds (E-4) using standard conditions known in the art (such as palladium on charcoal, with a stoichiometric amount of base such as Hunig's base under hydrogen).
  • Compounds of formula (E-4) may be prepared by reacting compounds (E-5) with a chlorinating agent such as POCl 3 and PCl 5 at elevated temperatures.
  • Compounds of formula (E-5) may be prepared by reacting compounds (E-6) with a suitable base (such as sodium methoxide) to induce cyclization to the quinazolines (E-5).
  • Compounds of formula (E-6) may be prepared by reacting compounds (E-7) with a suitable cyanate source (such as sodium cyanate) to yield the ureas (E-6).
  • the compound of formula (I) may be prepared by reacting compounds (F-1) with an alkyl halide of formula R 18 —X, wherein X is halo and R 18 is (C 1 -C 6 )alkyl in a suitable solvent (such as THF) with a suitable base (such as sodium hydride).
  • a suitable solvent such as THF
  • a suitable base such as sodium hydride
  • Compounds of formula (F-1) may be prepared by reacting compound (F-2) under deprotecting conditions known in the art (such as sodium ethanethiolate in DMF).
  • Compounds of formula (F-2) may be prepared by reacting compound (F-3) with sodium methoxide in methanol.
  • Compounds of formula (F-3) may be prepared by reacting compound 2-chloro-7-fluoro-quinazoline (F4) with various amines in a suitable solvent (such as acetonitrile) with a suitable base (such as DBU).
  • a suitable solvent such as acetonitrile
  • a suitable base such as DBU
  • the compound of formula (I) may be prepared by reacting compounds (F-3) with alcohols of formula R 19 —OH, wherein R 19 is (C 1 -C 6 )alkyl, in a suitable solvent (such as THF) with a suitable base (such as sodium hydride).
  • the compound of formula (I) may be prepared by reacting compounds (G-1) with an alkyl halide of formula R 20 —X, wherein X is halo and R 20 is (C 1 -C 6 )alkyl in a suitable solvent (such as THF) with a suitable base (such as sodium hydride).
  • a suitable solvent such as THF
  • a suitable base such as sodium hydride
  • Compounds of formula (G-1) may be prepared by reacting compound (G-2) under deprotecting conditions known in the art (such as sodium ethanethiolate in DMF).
  • Compounds of formula (G-2) may be prepared by reacting compound 2-chloro-8-methoxy-quinazoline (G-1) with various amines in a suitable solvent (such as acetonitrile) with a suitable base (such as DBU).
  • a suitable solvent such as acetonitrile
  • a suitable base such as DBU
  • a method for the preparation of the 2-amino-quinazoline-carboxamides is depicted in Scheme H.
  • Anilines of type H-1 are treated with a suitable cyanate source (such as sodium cyanate) to yield the ureas H-2.
  • a suitable base such as sodium methoxide
  • the hydroxyquinazolines were chlorinated using POCl 3 and PCl 5 at elevated temperatures to yield the 2,4-dichloro quinazolines H-4.
  • the mono chloro-quinazolines H-5 were obtained via selective dehalogenation of compounds H-4 using standard conditions known in the art (such as palladium on charcoal, with a stoichiometric amount of base such as Hunig's base under hydrogen), and the resulting compounds of type H-5 were treated with various amines in a suitable solvent (such as acetonitrile) with a suitable base (such as DBU) to afford the 2-amino quinazolines H-6.
  • the esters H-6 were hydrolyzed under standard conditions known I the art (such as aqueous sodium hydroxide in methanol) to the corresponding carboxylic acids H-7.
  • the acids H-7 were subjected to standard amide coupling conditions and/or methods known in the art (such as EDCl, HOBt, with a suitable base such as NMM) to afford the amides H-8.
  • a scheme for preparation of various quinazoline-8-ethers is shown in scheme K.
  • the 3-chlorobenzoic acid derivative K-1 was treated with a suitable hydroxide (such as potassium or sodium hydroxide) to afford the phenol K-2.
  • K-2 was then esterified under standard conditions (such as thionyl chloride treatment followed by methanol) to afford the methyl ester K-3 which was in turn treated with a suitable alkyl mesylate and base (such as potassium carbonate) to yield the phenyl ether K-4.
  • the nitro group was then reduced under standard conditions (such as Raney nickel under hydrogenation conditions) to give K-5, which was subsequently cyclised with sodium cyanate to afford the quinazoline core, K-6.
  • K-6 Chlorination of K-6 was achieved using POCl 3 to afford K-7, which was then hydrogenated to afford the mono chloro quinazoline, K-8.
  • K-8 was then subjected to standard nucleophillic amines together with a suitable base (such as DBU) to afford K-9 and K-10.
  • Template K-10 was treated with a suitable alkylating agent (such as acyl chlorides or sulphonyl chlorides, in the presence of a base such as triethylamine) to afford compounds K-12 and K-11 respectively.
  • a suitable alkyl halide in the presence of a base (such as potassium carbonate) to afford the alkylamines K-13.
  • scheme L A scheme for the preparation of 8-pyrrolidine-quinazolines is shown above as scheme L.
  • the anthranillic acid L-1 was cyclised to the quinazoline L-2 on treatment with sodium cyanate in acetic acid, followed by a suitable base (such as sodium hydroxide).
  • Chlorination of L-2 was achieved with POCl 3 and PCl 5 to give the template L-3.
  • Selective displacement of the 4-chloro was carried out with ammonia gas to give L-4, which in turn was treated with isoamyl nitrite to effect deamination to yield L-5.
  • the general route for the synthesis of 8-aryl quinazolines is shown in scheme M.
  • the 8-bromo quinazoline core L-6 was synthesised as described above in scheme E.
  • L-6 was subjected to standard Suzuki type couplings to generate the compounds of type M-1 and M-2.
  • the latter phenolic aryl compounds were elaborated by alkylation with alkyl halides to yield the ethers M-3 and M-4.
  • the N-Boc amines MA were deprotected under standard conditions (such as TFA) to afford the amine ethers M-5.
  • Shown in scheme N is the synthesis of the quinazoline-8-ether amides, N-14.
  • the aniline N-1 is acylated under standard conditions (such as acetic anhydride in acetic acid) to N-2.
  • N-2 is then subjected to standard nitration conditions (such as nitric acid) to afford the nitrobenzene derivative N-3.
  • N-3 is treated with potassium hydroxide to afford the phenol N4, which is in turn globally methylated under standard conditions (such as methyl iodide in the presence of a suitable base) to yield the ether-ester N-5.
  • Reduction of the nitro group under standard hydrogenation conditions to N-6 followed by cyclisation with urea yields the quinazoline N-7.
  • the organic phase washed with water (3 ⁇ 50 mL), then brine (1 ⁇ 30 mL). The organic layer was dried over magnesium sulfate, and filtered and the solvent reduced under vacuum.
  • the product was purified by a silica gel column with 100% EA to give about 40.0% of desired product of 2,2-diethoxyacetamidine (O-2).
  • the 2,2-diethoxyacetamidine (O-2) was dissolved in 6 ml of concentrated H 2 SO 4 (99.9%) and the reaction was stirred at 40° C. for 72 hours. The solution was neutralized by 1M NaOH aqueous to PH 7.0.
  • the crude was purified by silica gel column with 50:50 (petroleum ether: EA) to give final product O-1; yield from 13% to 70% depending on the substitution of phenyl methane amidine.
  • Shown in scheme P is the synthesis of intermediates compounds P-1 containing N-1,4-dioxaspiro[4.5]dec-8-yl-isoquinolin-3-amine.
  • isoquinolin-3-amine (O-1) (873 mg, 3.7 mmol) was dissolved in 10 ml THF in flask and NaH (133.0 mg, 5.5 mmol) was added. The mixture was stirred at ambient temperature for 20 min. to form the N-sodium salt solution, followed by addition of Ti(OPr) 4 (4.2 g, 14.8 mmol) and 1,4 cyclohexanedione ethylene ketal (1.2 g, 7.2 mmol).
  • Shown in scheme Q is the synthesis of intermediates compounds Q-1 containing 4-(isoquinolin-3-ylamino)cyclohexanone.
  • the (1,4-Dioxa-spiro[4.5]dec-8-yl)-(8-fluoro-6-methyl-isoquinolin-3-yl)-amine (P-1) (510.0 mg, 1.4 mmol) was dissolved in a solution of 20 ml of THF and 15 ml of 1 M HCl. The reaction was heated in 50° C. for 1 hour. LC/MS showed no more start material remained.
  • Shown in scheme R is the synthesis of intermediates compounds R-1 and R-2 containing cis and trans-4-(isoquinolin-3-ylamino)cyclohexanol.
  • the 4-(Isoquinolin-3-ylamino)-cyclohexanones (Q-1) and NaBH 4 was dissolved in MeOH with stirring for 2 hrs at 50° C.
  • LC/MS showed no more start material left and cis and trans products in about 1:1 ratio.
  • the solvent was evaporated and partitioned with EA/water.
  • the organic layers were evaporated.
  • the cis (R-1) and trans (R-2) products were separated by HPLC with a combined yield ranging from 70% to 85%.
  • the vials were capped and placed in a 50° C. heating block in fumehood, and stirred for 14 h. After cooling to room temperature, 3.0 eq of NaBH 4 suspended in THF was added to the above reaction vials, respectively, and stirred for 14 h. 2-methoxylethyl ether appeared to solubilize NaBH 4 better and can also be used for the reduction. Carefully, 2N HCl aqueous solution was added to allow the pH to reach 1 or 2. The mixture was stirred for 1 h, and then the pH was adjusted to 8 by adding 2N aqueous NaOH. Precipitate was removed by passing the mixture through a syringe filter. The filtrate was analyzed using LCMS which showed the yields of the desired products ranging from 40 to 70%.
  • the compounds of the present invention may have asymmetric carbon atoms.
  • Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
  • the compounds of formulas (I) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula (I) from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • Those compounds of formula (I) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula (I).
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
  • salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • the compounds of the present invention may also be useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycystic ovarian syndrome, obesity, hyperglycemia, hyperlipidemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman's Medical Dictionary (Xth Ed.).
  • the amino heterocyclyl compounds of formula (I) may be provided in suitable topical, oral and parenteral pharmaceutical formulations for use in the treatment of GK mediated diseases.
  • the compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs.
  • the compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations. Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets.
  • these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period.
  • a pharmaceutically acceptable enteric coating such as glyceryl monostearate or glyceryl distearate
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension.
  • excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan mono
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to know methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the amino heterocyclyl compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and other glycerides.
  • topical use preparations for example, creams, ointments, jellies solutions, or suspensions, containing the compounds of the present invention are employed.
  • the amino heterocyclyl compounds of formula (I) may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles.
  • Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines.
  • Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight.
  • a preferred dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed using glass-backed silica gel 60 F 254 precoated plates (Merck Art 5719) and eluted with appropriate solvent ratios (v/v). Reactions were assayed by TLC or LCMS and terminated as judged by the consumption of starting material.
  • TLC thin layer chromatography
  • TLC plates Visualization of the TLC plates was done with UV light (254 nM wavelength) or with an appropriate TLC visualizing solvent and activated with heat. Flash column chromatography (Still et al., J. Org. Chem., 1978, 43, 2923) was performed using silica gel 60 (Merck Art 9385) or various MPLC systems, such as Biotage or ISCO purification system.
  • Peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broadened; m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectra (MS) data were obtained using Agilent mass spectrometer with APCI or ESI ionization. Elemental microanalyses were performed by Atlantic Microlab Inc. and gave results for the elements stated within ⁇ 0.4% of the theoretical values.
  • Preferred compounds in accordance with the invention may be prepared in manners analogous to those specifically described below.
  • Et 2 O refers to diethyl ether.
  • DMF refers to N,N-dimethylformamide.
  • DMSO refers to dimethylsulfoxide.
  • MTBE refers to tert-butyl methylether.
  • Activation of (4-Methoxy-phenyl)-acetic acid is accomplished by treatment of the carboxylic acid in DMA (5 mL) with HATU (802.6 mg, 2.1 mmol) and triethylamine (388.2 mg, 3.8 mmol) at room temperature for 1 hour.
  • the 6-(1H-Pyrazol-4-yl)-isoquinolin-3-ylamine (200.0 mg, 0.9 mmol) was added and the mixture was stirred at 75° C. for 24 hours. The reaction was monitored by LC/MS. Evaporation of DMA gave a residue that was washed with NaHCO 3 to remove the by-products from HATU.
  • a 12-L, 3-necked round bottom flask, equipped with a large stirrer bar, dropping funnel and thermometer was charged with water (5 L).
  • the flask was placed in an IPA bath and cooled externally with solid CO 2 to an internal temperature of 8° C. Over a period of 13 ⁇ 4 h, the reaction mixture was added slowly to the water, keeping the internal temperature between 0° C. and 10° C., resulting in a yellow suspension. With continued cooling, a 12 M NaOH solution was added over a 4 h period, keeping the internal temperature below 30° C. A final pH of 9-10 was reached (required 4.6 L, 12 M NaOH). Note that upon reaching neutral pH, the suspension changed to a much darker yellow.
  • the suspension was filtered over a medium glass filter and the remaining residue was washed repeatedly with a total of 4 L of water to wash away precipitated Na-salts which resulted in a significant decrease of the amount of solids on the filter.
  • the residue was dried in high vac at room temperature over KOH to give 143 g of a yellow powder. Elemental analysis showed 5.9 weight % of Na which corresponds to 36.4 weight % of Na 2 SO 4 . This material was used for further elaboration.
  • the reaction mixture was heated to rfx (internal temperature 80° C.) for a period of 16 h and allowed to cool to room temperature.
  • the cooled reaction mixture appeared as a two-layer system with a virtually colorless, aqueous layer and a dark organic layer in which a light brown precipitate had formed.
  • the reaction mixture was filtered over a short path of Celite (pre-wetted with MeOH) and the Celite was subsequently washed with DME (110 mL). Removal of the solids improved visibility and the water layer could be readily separated.
  • the organic layer was further diluted with ethyl acetate (700 mL) resulting in the separation of more solids which were remove by short-path filtration over a fresh batch of Celite (pre-wetted with MeOH).
  • the filtrate was concentrated to a volume of 30 mL and the formed solids were isolated by filtration and washed with diethyl ether (40 mL) to give 4.8 g (11%) of the desired product as a yellow solid.
  • Tin (II) Chloride (28.0 g, 147.7 mmol) and concentrated HCl (10 mL) were added sequentially to the solution of 1-trimethylanyloxy-4,5-dimethoxyindane-1-carbonitrile (33.1 g, 113.6 mmol) in acetic acid (100 mL).
  • the reaction mixture was heated to 86° C. for 7 h. After cooled to room temperature, acetic acid was removed in vacuo. The residue was dilute by 200 mL of water, followed by addition of concentrated HCl to PH ⁇ 1.
  • the water layer was extracted by EtOAc (300 mL ⁇ 3), the combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the resulting yellow gum was purified directly by Biotage 25M; loaded in 2% MeOH/CH 2 Cl 2 , and eluted with 2-7% MeOH/CH 2 Cl 2 over 520 mL. Product not fully eluted so continued over another 300 mL to 10% MeOH/CH 2 Cl 2 to give a solid that was then triturated with EtOAc, filtered and dried in vacuo to yield the title compound as a yellow solid, 78 mg, 65%.
  • the resulting yellow gum was purified directly by Biotage 25M; loaded in 2% MeOH/DCM, and eluted with 2-7% MeOH/DCM over 520 mL. Product not fully eluted so continued over another 300 mL to 10% MeOH/DCM to give a solid that was then triturated with EtOAc, filtered and dried in vacuo to yield the title compound as a yellow solid, 78 mg, 65%.
  • trans-4-[(8-bromoquinazolin-2-yl)amino]cyclohexanol (322 mg, 1 mmol), followed by Pd(OAc) 2 (48 mg, 0.2 mmol), (o-Tol) 3 P (60 mg, 0.2 mg), Ag 2 CO 3 (192 mg, 0.7 mmol), toluene (8 mL) and i Pr 2 NEt (516 mg, 4 mmol), followed by 1-(methylsulfonyl)-2,5-dihydro-1H-pyrrole (560 mg, 3.8 mmol). The mixture was refluxed overnight under Ar. TLC showed that several new spots were formed with small amount of starting material remaining.
  • 6-bromo-8-methylisoquinolin-3-amine was also prepared using the Scheme 0.4.1 g of SM provided 2.8 g of crude product. 0.87 g of pure product was obtained using a silica gel column purification.
  • 1H NMR 400 MHz, DMSO-d6) ppm, 2.58 (s, 3H), 6.09 (s, 2H), 6.55 9 s, 1H), 7.63 (s, 1H), 8.91 (s, 1H).
  • Scheme P was used in the preparation of 3-(1,4-dioxaspiro[4.5]dec-8-ylamine)-8-methyl-6-bromo-isoquinoline.
  • the crude material was purified by a silica gel column with 50:50 (EtAc/Petroleum) to give 730.0 mg of the desired product (yield 52.1%).
  • 1H NMR 400 MHz, DMSO-d6) ppm, 2.58 (s, 3H), 6.09 (s, 2H), 6.55 9 s, 1H), 7.63 (s, 1H), 8.91 (s, 1H).
  • trans-4- ⁇ [5-(cyclopentyloxy)-8-methylisoquinolin-3-yl]amino ⁇ cyclohexanol was prepared 5-(cyclopentyloxy)-N-1,4-dioxaspiro[4.5]dec-8-yl-8-methylisoquinolin-3-amine by using the Schemes Q and R described above.
  • the crude product was purified by prepHPLC to give 84.0 mg, yield 39.4%, and the cis-isomer described below.
  • N-1,4-dioxaspiro[4.5]dec-8-yl-5-fluoro-8-methylisoquinolin-3-amine was prepared by using the Scheme P.
  • the crude residue was purified by a silica gel column to give product 1.3 g.
  • cyclopentanol 600.0 mg, 7.0 mmol was dissolved in 5 ml of THF. To this solution was added the NaH (273.0 mg, 11.4 mmol) at room temperature and the mixture was stirred for 30 min. N-1,4-dioxaspiro[4.5]dec-8-yl-5-fluoro-8-methylisoquinolin-3-amine (1.8 g, 5.7 mmol) mixed with 15-crown-5 ether (0.13 g, 0.57 mmol) in 15 ml of DMSO was added to above solution. The microwave test tube was capped and moved out from the dry box. The tube was placed into Microwave apparatus and heated to 140° C.
  • N-1,4-dioxaspiro[4.5]dec-8-yl-7-fluoro-5-(trifluoromethyl)isoquinolin-3-amine was prepared by using the Scheme P.
  • the crude material was purified by a silica gel column to give 1.3 g, yield of 13.0% from 6.2 g of 7-fluoro-5-(trifluoromethyl)isoquinolin-3-amine.
  • Scheme R was used for the preparation of both trans and cis products.
  • the crude product was purified by SFC to give Trans-4- ⁇ [7-fluoro-5-(trifluoromethyl)isoquinolin-3-yl]amino ⁇ cyclohexanol 37.1 mg, 30.1%, and cis-isomer described below.
  • a coupled spectrophotometric assay coupling JNK1 ⁇ 1 activity to the oxidation of ⁇ -NADH to NAD+ through the action of pyruvate kinase (PK) and lactic dehydrogenase (LDH), was used to determine the potency (percent inhibition at 1 or 10 ⁇ M or K i ) of compounds against JNK1 ⁇ 1 (Genbank Accession Number: L26318).
  • PK pyruvate kinase
  • LDH lactic dehydrogenase
  • the final reaction conditions were as follows: 20 mM HEPES pH 7.6, 10 mM MgCl 2 , 1 mM DTT, 200 ⁇ M peptide substrate (KRELVEPLTPSGEAPNQALLR), 300 ⁇ M NADH, 500 ⁇ M PEP (phophoenolpyruvate), 9-10 units/mL LDH, 8-12 units/mL PK, 40 nM JNK1 ⁇ 1 — 364nHis (catalytic domain containing amino acids 1-364 and N-terminal hexahistidine tag, previously activated by MKK4 and MKK7beta in vitro), 0-100 ⁇ M test compound, 2.5% DMSO, and 50 ⁇ M ATP (2.5 ⁇ Km).
  • the reaction was monitored by following the decrease in absorbance at 340 nm.
  • the initial reaction rate was determined by the slope of the change in absorbance.
  • percent inhibition the rate of the reaction in the presence of 1 or 10 ⁇ M compound was compared to the rate of the reaction with only DMSO multiplied by 100 percent. Note, the background rate of the above reaction in the presence of 10 ⁇ M PHA-00738186 was subtracted from all rates.
  • K i the reaction rates (with the background subtracted) were plotted vs. the compound concentration (0-100 ⁇ M) and fit to the tight binding for competitive inhibitors (Morrison) equation (see below).
  • the compounds were prepared in 100% DMSO at a 40 ⁇ concentration. For percent inhibition experiments this would be 400 or 40 ⁇ M for 10 and 1 ⁇ M final concentration, respectively.
  • Ki determination 3 ⁇ serial dilutions were made starting at 4 mM (100 ⁇ M at 1 ⁇ ) in DMSO. A total of 11 concentrations were used for the analysis.
  • the compounds were added to the reaction plate first.
  • a solution containing the HEPES, MgCl 2 , DTT, peptide substrate, NADH, PEP, PK/LDH enzyme, and JNK1 ⁇ 1 — 364nHis enzyme was added to the assay plate.
  • the plate was incubated at room temperature for 15 minutes. Then the plate was warmed to 30° C. for 5 minutes.
  • the reaction was initiated with the addition of ATP.
  • the reaction was run in a plate reader at 30° C. for 20 minutes with absorbance readings made about every 10 seconds.
  • BL21 (DE3) cells containing JNK1 ⁇ 1 — 364nHis vector were grown at 37° C. until optical density (OD 600 ) was between 0.6 to 0.8. Expression was induced by addition of isopropylthiogalactoside (IPTG) to a final concentration of 0.1-0.2 mM and incubated at 23° C. overnight. The cells were harvested at 5000 rpm for 15 minutes at 4° C. The cell pellet can be stored at ⁇ 80° C. for future purification.
  • IPTG isopropylthiogalactoside
  • Lysis Buffer 1 L 25 mM Tris-HCl, pH 8.0 25 mL of 1M 300 mM NaCl 60 mL of 5M 14 mM ⁇ -ME (add fresh) 1 mL of 14M stock 20 mM Imidazole 5 mL of 4M dH 2 O 909 mL
  • BP break point
  • % B means % buffer grading
  • FR means flow rate
  • FS fraction size
  • BP break point
  • FR flow rate
  • FS fraction size
  • I inject
  • L load
  • the Ni-NTA column was washed with 80 mL of dH 2 O at 5 mL/min. Next it was washed with 80 mL of 0.1M EDTA, pH8.0 at 5 mL/min. The flow was collected through in flask for proper disposal. The column was further washed with 150 mL of dH 2 O at 5 mL/min. and charged with 60 mL of 100 mM NiCl 2 at 5 mL/min. The flow was collected through in the same waste flask. The column was then washed with 60 mL of dH 2 O at 5 mL/min and the flow was again collected through in the same waste flask. The column was then washed with 160 mL of dH 2 O at 5 mL/min.
  • the Superdex 200 column was washed with 700 mL of filtered dH 2 O at 2 mL/min.
  • the data obtained from the compounds of the invention according to the above protocol are tabulated below.
  • the column with “#” heading refers to compound number as exemplified in the Examples section.
  • the column with “Ki” heading refers to Ki (in nM).
  • the column with “% Inhibition” heading refers to percent inhibition of JNK-1 at 1 ⁇ M or 10 ⁇ M (in %) unless otherwise stated. ND refers to no data was taken.

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